4 départements de recherche
750 employés
45 nationalités
55 équipes de recherche
16 lauréats ERC
260 publications par an
24000 m² de laboratoires

Soutenez-nous via

Fondation universite de Strasbourg

photo

Chef d'équipe

Yvon TROTTIER
yvon.trottier@igbmc.fr
Tel. : +33 (0)3 88 65 32 68

Les chiffres

52 équipes de recherche
134 chercheurs
95 post-doctorants
132 doctorants
194 ingénieurs & techniciens
22 masters
132 administratifs & services généraux 110 personnels ICS

Accès direct

Recrutement

Molecular Basis Of Transcriptional Dysregulations In The Spinocerebellar Ataxia 7, A Neurodegenerative Polyglutamine Disorder.

Reference : PhD Yvon Trottier

Publication de l'offre : 22 juillet 2016

Our team is interested in deciphering the pathomechanisms of a group of 9 inherited neurodegenerative disorders –including Huntington’s disease and several SpinoCerebellar Ataxia (SCA)- that are caused by the expansion of a polyglutamine (polyQ) motif in disease proteins. It is widely accepted that polyQ expansion conveys a toxic gain-of-function to the affected protein, leading to transcriptional alterations. However, the mechanisms underlying gene deregulation are yet unclear, while they could represent potential targets for development of therapeutic strategies.

 

SCA7 is caused by polyQ expansion mutation in Ataxin-7,  which is a subunit of the SAGA multiprotein complex. SAGA regulates transcription by acetylating histone H3K9 through the activity of its GCN5 subunit and by deubiquitinating histone H2Bub through the activity of USP22. SAGA was recently shown to be a bone fide cofactor for all RNA polymerase II transcription (Bonnet et al. Gene Develop. 2014). The distinctive feature of SCA7 among polyQ diseases is the progressive cone-rod degeneration responsible for blindness in SCA7 patients. The SCA7 pathology has been modeled in different mouse models. Noteworthy, studies of the retina, which provides a simple and accessible CNS tissue, have been extremely powerful to delineate a close correlation between progressive reduction of electroretinograph activity, profound morphological changes of photoreceptor cell shape and transcriptional alterations (Yvert et al. HMG 2000; La Spada et al. Neuron 2001; Yoo et al, Neuron 2003; Yefimova et al. Neurobiol. Dis 2010). In particular, the expression profile of SCA7 mice unveiled the alteration of genetic programs controlling the maintenance of photoreceptor identity (polarity and outer segment formation) (Abou-Sleymane et al. HMG 2006). Furthermore, photoreceptor nuclei show a massive chromatin decondensation (Helmlinger et al. PloS Biol. 2006), suggesting that epigenetic perturbations affecting chromatin 3D organization account for major changes in gene expression. However, the precise mechanisms whereby mutant ATXN7 compromises the genetic programs of photoreceptor identity are yet unclear.

 

The main objective of the PhD project is  to determine the genetic basis of cell-type specific gene dysregulation in SCA7 photoreceptors by integrating genomic, epigenomic and gene expression analyses. To this aim, the PhD candidate will compare homozygotes SCA7 knock-in mice with their wildtype littermates and use Laser capture microdissection to study specifically the population of photoreceptors. She/he will perform RNA-seq and ChIP-seq analyses using antibodies against different epigenetic marks, as well as methylome and ATAC experiments to explore in a genome wide manner genes, promoters and superenhancers in relation with patterns of DNA methylation and chromatin accessibility. The project will reveal the molecular basis of the loss of neuronal identity and dysfunction in SCA7 and provide the groundwork to address transcriptional dysregulations in other polyQ disorders.

 

At the end of the thesis program, the PhD candidate will master a large range of biochemical and molecular biology techniques, dedicated to explore genomic and epigenomic changes in relation with neurodegenerative conditions.

 

COMPETENCES SOUHAITEES :

-Interest in neurodegenerative processes and translational research
- Basic knowledge in biochemistry, molecular and cellular biology

- Previous training period in a research laboratory
- autonomy and ability to work within a research group

EXPERTISES QUI SERONT ACQUISES AU COURS DE LA FORMATION :

- methodologies for genomic, epigenomic and gene expression analyses

- bioInformatic analysis for data integration
- ability to design and conduct experimentations (strategy choice, realization, analysis, validation)
- Communication of results through publication and scientific meeting
- participation to writing research grant application

 

Votre candidature

Date limite de candidature : 31 décembre 2016

Imprimer Envoyer

Université de Strasbourg
INSERM
CNRS

IGBMC - CNRS UMR 7104 - Inserm U 964
1 rue Laurent Fries / BP 10142 / 67404 Illkirch CEDEX / France Tél +33 (0)3 88 65 32 00 / Fax +33 (0)3 88 65 32 01 / directeur.igbmc@igbmc.fr